The invention herein relates to a pharmaceutical composition comprising ticlopidine and Ginkgo biloba extract. In detail, as an anti-thrombotic preparation, the pharmaceutical composition comprising said ticlopidine and Ginkgo biloba extract with the PAF-antagonistic and anti-oxidant actions is used in combination to naturally suppress the neutropenia and agranulocytosis caused by the toxicity resulting from the repeated use of ticlopidine alone.
As a platelet aggregation inhibitor belonging to the thienopyridine group, ticlopidine is widely used clinically. Unlike aspirin, ticlopidine does not affect the production of prostacycline-thromboxane A2. Further, metabolites such as 2-hydroxyticlopidine (2-HT) inhibit the platelet aggregation induced by ADP, collagen, arachidonic acid, thrombin, or PAF, which in turn stimulate the expression of the glycoprotein IIb/IIIa receptors on platelets. Glycoprotein IIb/IIIa, a fibrinogen receptor on the plasma membrane of platelets, is required for the formation of a plug via platelet aggregation. By suppressing the expression of the glycoprotein IIb/IIIa receptors, ticlopidine inhibits the platelet aggregation therein. Consequently, the suppression is put to an effect as if the platelets were in anesthesia.
Further, ticlopidine decreases the viscosity of blood by means of reducing fibrinogen in the plasma in conjunction with an increase in the plasticity of the red blood cells.
As such, ticlopidine is a synthetic drug which suppresses the functions of the platelets. The drug is widely used for the purposes of clinically preventing a stroke coupled with thrombosis and arteriosclerosis, ischemic heart diseases such as angina, intermittent claudication, etc.
However, if ticlopidine is repeatedly used by itself, the problem arises in which the major side-effects are reversible neutropenia and agranulocytosis. Neutropenia is defined as neutrophil counts in blood falls below 1200/mm3. Agranulocytosis is defined as neutrophil counts in blood falls below 450/mm3.
Aforementioned toxicity manifests in the patients at the incidence rate of 0.8% during the first 3 months of treatment. Although the granulocyte, colony-stimulating factor can be used to improve the situation, this cannot be the fundamental solution. Consequently, aspirin is used as a primary drug for a stroke, etc, and ticlopidine is used as a secondary drug in the case of patients who are intolerant to aspirin.
In worsening condition, ticlopidine may cause bone-marrow toxicity with the result of thrombocytopenia, which in return causes purpura or prolongation in hemorrhage period. The problem can be further complicated by the manifestation of aplastic anemia.
On the other hand, in the case of clozapine with respect to the similar problem of neutropenia as in ticlopidine, L-ascorbic acid which is an anti-oxidant has been used in combination to improve the situation. [Korea Patent Application No. 97-700915] However, this method is not preferable since L-ascorbic acid only has the anti-oxidant action without increasing the effect of clozapine.
In order to solve various problems when ticlopidine is used alone as an anti-thrombotic preparation, the Ginkgo biloba extract with anti-oxidant action and platelet aggregation inhibition effect are used in combination with said ticlopidine. As such, the objective of the present invention is to provide a new pharmaceutical composition comprising ticlopidine and Ginkgo biloba extract, which has the effect of decreasing neutropenia toxicity in addition to improving the inhibition of platelets aggregation.